chr8-22404768-G-A

Position:

• chr8-22404768-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_015359.6(SLC39A14):​c.58G>A​(p.Gly20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SLC39A14 NM_015359.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.321

Genes affected

SLC39A14 (HGNC:20858): (solute carrier family 39 member 14) This gene encodes a member of the the SLC39A family of divalent metal transporters that mediates the cellular uptake of manganese, zinc, iron, and cadmium. The encoded protein contains eight transmembrane domains, a histidine-rich motif, and a metalloprotease motif, and is expressed on the plasma membrane and the endocytic vesicle membrane. It is an important transporter of nontransferrin-bound iron and a critical regulator of manganese homeostasis. Naturally occurring mutations in this gene are associated with neurodegeneration with brain iron accumulation and early-onset parkinsonism-dystonia with hypermanganesemia. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042354792).
• BP6: Variant 8-22404768-G-A is Benign according to our data. Variant chr8-22404768-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1470060.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC39A14	NM_001128431.4	c.58G>A	p.Gly20Ser	missense_variant	2/9	ENST00000381237.6
SLC39A14	NM_015359.6	c.58G>A	p.Gly20Ser	missense_variant	2/9	ENST00000359741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC39A14	ENST00000359741.10	c.58G>A	p.Gly20Ser	missense_variant	2/9	2	NM_015359.6	A2
SLC39A14	ENST00000381237.6	c.58G>A	p.Gly20Ser	missense_variant	2/9	1	NM_001128431.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461632 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 20 of the SLC39A14 protein (p.Gly20Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1470060). This variant has not been reported in the literature in individuals affected with SLC39A14-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.086
DANN	Benign	0.44
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.64	T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.042	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N;.;N;N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.33	N;N;N;N;N;N;D;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.76	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.0	.;.;B;B;B;.;.;.;.;.
Vest4		0.085
MutPred		0.49		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.048
MPC		0.55
ClinPred		0.033	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.014
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-22262281;